B-cell neoplasms are a heterogeneous group of diseases characterized by different maturation states of the B-cell, which are related to the aggressiveness of the disorder. Accordingly, the lymphomas are classified into three groups: low grade, intermediate grade and high grade lymphomas. The "low grade" nodular lymphocytic, well-differentiated lymphoma is occasionally confused with chronic lymphocytic leukemia because of the identical histologic picture.
Chronic lymphocytic leukemia (CLL) is characterized by proliferation and accumulation of B-lymphocytes that appear morphologically mature but are biologically immature. CLL typically occurs in persons over 50 years of age. This disorder accounts for 30% of leukemias in Western countries, with 10,000 new cases being diagnosed annually in the United States alone.sup.(1).
The disorder is characterized by proliferation of biologically immature lymphocytes, unable to produce immunoglobulins, which upon organ infiltration cause lymph-node enlargement and hepato-splenomegaly. In the advanced stages of the disease, bone marrow occupation by the abnormal lymphocytes results in bone marrow failure, resulting in anemia and thrombocytopenia.
The B-cells in CLL have receptors for mouse erythrocytes, a marker of immature B-cells. An increased number of T-cells has been reported in this disorder with an increase in the number of T-suppressor cells.sup.(2-5). Some data support the possibility that B-CLL cells secrete an inhibitory factor that suppresses T-cell function.sup.(6). In addition, in 50% of CLL patients, chromosome analysis provides prognostic information about overall survival, in addition to that supplied by clinical data in patients with B-cell CLL.sup.(7).
Several cytokines have been reported to stimulate the growth of B-cells in general, such as interleukin-1.sup.(8) and interleukin-6.sup.(9-11) (hereinafter IL-6), while tumor necrosis factor (TNF) have been shown to serve as an autocrine tumor growth factor for the pathological B-cells in CLL.sup.(12, 13).
IL-6 has been found to serve also as a growth stimulatory factor for certain B-cell neoplasms such as plasmacytoma, myeloma cells and derived hybridomas.sup.(9-11) or for Epstein-Barr virus (EBV)-transformed B lymphocytes.sup.(17). In B-cell CLL, constitutive expression of the IL-6 gene was found, but the biological significance of IL-6 expression in B-CLL was not fully elucidated.sup.(14).
As mentioned above, TNF has been shown to serve as an autocrine tumor growth factor for B-cell CLL.sup.(12, 13), prolonging the survival of B-cell CLL cells and inducing them to proliferate.sup.(15).
mRNA for IL-6 is induced by TNF in B-CLL cells; this cytokine could then be the agent responsible for the proliferative events of the leukemic cells. If B-cell CLL is dependent on autocrine growth factors for survival, interruption of the autocrine loop would be of therapeutic value.sup.(15). Such interruption of the autocrine growth-stimulating loops was obtained with interferon-.alpha..sup.(16), yet administration of this cytokine to CLL-patients was not beneficial.
IL-6 does not promote the growth of normal B-lymphocytes. Since the growth effect of IL-6 is seen in EBV transformed cells or in B-cell tumors, it was anticipated that the growth of leukemic B-cells from CLL patients will also be stimulated by this cytokine.